Stroke is a leading cause of long-term disability in the United States. It is well established that poor motor rehabilitation outcomes are associated with elevated neural activity in the contralesional hemisphere when stroke patients are using their affected limb. The overarching goal of this project is to determine the neurobiologic basis for this elevated activity in the contralesional primary motor cortex in these patients. It is possible that this elevated activity is due to changes in cortical excitability within the contralesional hemisphere (tested in Aim 1) as well as alterations in signal conduction between the hemispheres (tested in Aim 2). In addition to examining the contribution of within and between hemisphere signaling to elevated neural activity in the contralesional hemisphere, we will also determine the extent to which these neurobiological factors contribute to clinically relevant outcomes - such as unimanual and bimanual motor performance (Aim 3). We will use a multimodal approach (including brain imaging/brain stimulation (Interleaved TMS/BOLD imaging), magnetic resonance spectroscopy and clinical assessment) to address these Aims in a cross-sectional cohort design of hemiparetic chronic stroke patients with right-sided upper extremity weakness subsequent to a left hemisphere cortical stroke, as well as a group of neurologically healthy, age-matched controls. The results of these Aims will clarify the relative contribution of within and between hemisphere adaptations to cortical reorganization. These data will provide a foundation a longitudinal R01 that will determine which patterns of laterality predict favorable treatment outcomes, and will also add to the basic science interpretation of Dr. Malcolm (Project 2) and Dr. Feng's (Project 3) SCRCRS projects.